ABSTRACT Detailed specificity analysis is critical for drugs, as even minimal off-target binding can cause serious adverse events. As a result, specificity profiling has become an FDA requirement for monoclonal antibodies (MAbs) as well as other emerging biotherapeutic categories such as CAR-T cell therapy. Current methods for profiling the specificity of biotherapeutics, primarily tissue cross-reactivity studies and spotted protein arrays, are poorly predictive of cross-reactivity against the native human proteome, have low sensitivity, and are difficult to interpret. A novel approach for specificity profiling is needed to better predict off-target binding of MAbs and de- risk biotherapeutic discovery programs. Here we propose to develop a technology that has the predictive validity to de-risk biotherapeutics entering preclinical development. This product would have a large impact on the clinical pipelines of nearly every biopharmaceutical company, has significant commercial potential, and can be implemented with very low risk. The resulting product will be the first major innovation in in vitro toxicology testing for biotherapeutics since tissue cross-reactivity studies were adopted 35+ years ago.